ADIPOCYTE GROWTH AND PATHOGENESIS OF LIPOSARCOMA

脂肪细胞的生长和脂肪肉瘤的发病机制

• 批准号: 6376022
• 负责人: DAVID RON
• 金额: $ 31.07万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-07-15 至 2003-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6376022
• 关键词: RNA binding protein; adipocytes; cell growth regulation; chimeric proteins; chromosome translocation; genetic promoter element; genetic transcription; genetically modified animals; laboratory mouse; liposarcoma; molecular oncology; neoplasm /cancer genetics; neoplastic transformation; oncogenes; oncoproteins; pathologic process; reporter genes; tissue /cell culture; transcription factor; yeast two hybrid system; RNA binding protein; adipocytes; cell growth regulation; chimeric proteins; chromosome translocation; genetic promoter element; genetic transcription; genetically modified animals; laboratory mouse; liposarcoma; molecular oncology; neoplasm /cancer genetics; neoplastic transformation; oncogenes; oncoproteins; pathologic process; reporter genes; tissue /cell culture; transcription factor; yeast two hybrid system

DESCRIPTION: This project explores the molecular mechanisms involved in cellular transformation by the chimeric transcriptional regulatory protein TLS-CHOP that is encoded by the t(12:16) chromosomal rearrangement common to most myxoid and round cell liposarcomas. It is hypothesized that transformation in liposarcoma proceeds by two parallel pathways: (1) The CHOP component of the oncoprotein directs it to one set of target genes, and the TLS component deregulates their expression; (2) TLS-CHOP impinges on the normal function of the RNA-binding protein TLS, interfering with the proper expression of another set of target genes. The second component is predicted to be common to sarcomas that contain a TLS (or EWS) component in their causative oncoprotein. Members of both sets of target genes are hypothesized to function as effectors of the process of transformation. The goals of this project are, thus, to identify TLS-CHOP target genes, delineate the mechanism of their deregulation in liposarcoma, and determine their role in transformation. This will involve identifying genes contacted by TLS-CHOP and genes that are normally regulated by TLS, as well as identifying proteins that participate as partners in the process by which TLS-CHOP carried out its function. The latter include the direct cellular contingents of TLS and CHOP, as well as the products of genes that modify transformation indirectly. The identification of TLS-CHOP and TLS target genes will rely on the comparative analysis of the expression pattern of genes in cells that do and do not contain active forms of these regulators. The direct contingents of TLS and CHOP will be identified by biochemical and genetic means, whereas the identification of genes that modify the process of transformation by TLS-CHOP will be attained by a genetic screen of tumors derived in genetically-modified mice that will be developed as animal models for tumorigenesis by the oncoprotein.

描述：该项目探讨了所涉及的分子机制 嵌合转录调节蛋白的细胞转化 TLS-CHOP由T（12:16）染色体重排编码 大多数粘液样和圆形细胞脂肪肉瘤。 假设 脂肪肉瘤中的转化通过两个平行途径进行：（1） 癌蛋白的切碎成分将其引导到一组靶基因，并将其引导 TLS成分消除其表达； （2）TLS-CHOP撞击 RNA结合蛋白TL的正常功能，干扰适当的 表达另一组靶基因。 第二个组件是 预计包含TLS（或EWS）组件的肉瘤常见 它们的致病性癌蛋白。 两组靶基因的成员都是 假设可以充当转化过程的效应子。 这 因此，该项目的目标是确定TLS-Chop靶基因， 描述其在脂肪肉瘤中放松管制的机制，并确定 它们在转型中的作用。 这将涉及识别联系的基因 通过通常由TLS调节的TLS-CHOP和基因 识别参与合作伙伴参与的蛋白质的过程 TLS-Chop执行了其功能。 后者包括直接细胞 TLS和CHOP的偶像以及修饰的基因产物 间接转化。 TLS-CHOP和TLS目标的识别 基因将依赖于对表达模式的比较分析 在且不包含这些调节剂的活性形式的细胞中的基因。 TLS和CHOP的直接偶像将通过生化和 遗传手段，而鉴定改变过程的基因 TLS-CHOP转化将通过肿瘤的遗传筛选来实现 衍生在遗传改性的小鼠中，该小鼠将作为动物模型开发 用于肿瘤蛋白的肿瘤发生。